The invention relates to the use of imino acid conjugates of methylglyoxal for the inhibition and/or treatment of cancer. The invention relates more specifically to the use imino acid conjugates of methylglyoxal for inhibition and/or treatment of cancer of the Colon, Prostate, Larynx, Kidney, Pancreas, Lung, Breast, Intestine, Oral cavity, Ovary, Glioblastoma, and Leukemia. The anticancer activity of the conjugates is attributed to the inhibition of the activity of glyceraldehyde 3 phosphate dehydrogenase enzyme. The invention also relates to compositions and methods of inhibiting cancer using imino acid conjugates of methyglyoxal.
As early as 1913 it had been observed that ketoaldehydes such as, methylglyoxal could be converted to corresponding hydroxyl acids (methylglyoxal to D-lactate) by strong and ubiquitous enzyme present in various animal tissues. It was then widely held that methylglyoxal was a key intermediate of glucose breakdown. But with the elucidation of Embden-Meyerh of pathway of glycolysis, this idea was rejected. Although no definite enzyme was identified or isolated, several investigators time to time reported the formation of methylglyoxal in different organisms (Current Science 75, 103-113; 1998).
Cooper and his co-investigators established that the enzyme methylglyoxal synthase which converts the glycolytic intermediate dihydroxyacetone phosphate to methylglyoxal is present in a variety of bacteria (Annu Rev Microbiol 38, 49-68; 1984). In the early 1980s, Ray and Ray began a thorough investigation of the enzymes involved in the synthesis and breakdown of methylglyoxal in a mammalian system. Mainly by their work and also by the investigations from other laboratories, the metabolic pathway of methylglyoxal in a mammalian system had been established. In the process, they had isolated, purified and partially characterized a battery of enzymes involved. Thereafter the pathway for methylglyoxal metabolism has been elucidated in yeast, bacteria and protozoa (Current Science 75, 103-113; 1998).
High capacity for aerobic glycolysis is an essential characteristic of rapidly growing malignant cells (Baggetto, 1992, Biochimie 74, 959-974, 1992). Methyl glyoxal inactivates glyceraldehyde 3 phosphate dehydrogenase, a key enzyme in the glycolytic pathway, leading to a critical reduction in the levels of ATP in cancerous cells (Ray et al, Molecular and Cellular Biochemistry 177, 21-26,1997). Glyceraldehyde 3 phosphate dehydrogenase catalyzes the phosphorylation of D-glyceraldehyde 3 phosphate to 1,3 biphosphoglycerate. There has been significant literature to suggest the role of glyceraldehyde 3 phosphate dehydrogenase in malignant conditions viz. in lung cancers (Tokunaga et al, 1987, Cancer Research 47, 5616-5619), pancreatic cancers (Schek et al 1988, Cancer research 48, 6354-6359 ), breast cancers (Deasprez et al, 1992, Cancer lett 64, 219-224) and prostate cancers (Epner et al, 1993, Cancer research, 1993, 53, 1995-1997). The kinetics and structure of glyceraldehyde 3 phosphate dehydrogenase enzyme may be critically altered in malignant cells (Bagui et al, 1999, Eur J Biochem 262, 386-395). Glyceraldehyde 3 phosphate dehydrogenase expression is altered in hypoxia (Graven et al, 1994, J. Biol Chem, 269, 24446-24453), in oncogene transformed cells (Persons et al, 1989, Mol. Carcinogenesis, 2, 88-94), and varies with the cell cycle (Mansur et al, 1993, Nucleic Acids Res, 21,993-998). In view of the reported inhibition of glyceraldehyde 3 phosphate dehydrogenase by methyl glyoxal, and its role as a critical glycolytic enzyme altered in malignant cells, we investigated its modulation by the methyl glyoxal conjugates covered in this study.
Egyud and Szent-Gyorgyi showed that methylglyoxal could inhibit tumor development in mice when it was injected into mice along with sarcoma 180 cells (Science 160, 1140; 1968). It was recently demonstrated that methylglyoxal inhibits the proliferation of Ehrlich ascites carcinoma (EAC) cells and leukemia cells. However, the broad spectrum of its anticancer activity has not been investigated so far. Neither is there any report on the antiangiogenic potential of methylglyoxal.
Much work has been carried out on the conjugates of methylglyoxal. U.S. Pat. No. 4,066,650 discloses the addition products between ketoaldehydes and secondary amines. The patent describes method of preparation of the addition products and the pharmaceutical compositions for the treatment of cancer. U.S. Pat. No. 4,238,500 describes the novel condensation products of (xcex1-ketoaldehyde with enediol and their pharmaceutical uses as anticancer, antihypotensive and analgesic compounds. U.S. Pat. No. 5,147,652 describes the liposome encapsulated ketaoaldehydes and their pharmaceutical use for the treatment of cancer and other non-self cells. U.S. Pat. No. 5,849,783 describes the physically and chemically latentiated methylglyoxal or xcex1-ketoaldehydes for treating the non-self cells which includes cancer.
The present invention relates to the class of novel conjugates of methyl glyoxal with alkyl/aryl esters of imino acid, a process for preparing them and use of these compounds for the treatment of cancer.